tbuckley/cabot-search huggingface dataset:
Test Performance of Cervical Cytology Among Adults With vs Without Human Papillomavirus Vaccination
Authors: Deanna Teoh, Gwiwon Nam, Danielle A. Aase, Ruby Russell, Genevieve B. Melton, Shalini Kulasingam, Rachel I. Vogel
Journal: JAMA Network Open (2022)

Current US cervical cancer screening guidelines do not differ by human papillomavirus (HPV) vaccination status. However, as the positive predictive value (PPV) of a screening test decreases, the risk of a false-positive result increases.To evaluate whether HPV vaccination is associated with decreased PPV for abnormal cervical cytology.This retrospective cohort study conducted via electronic medical record review included eligible patients aged 21 to 35 years who had at least 1 cervical cytology result within a single health system between January 2015 and December 2018. The health system comprises a partnership between an academic health center and a private not-for-profit health center. Patients with abnormal screening cytology and no diagnostic test results were omitted from analysis. Data were analyzed from December 2019 to November 2021.HPV vaccination, defined as receiving at least 1 dose of HPV vaccine. Subgroup analyses were performed for those completing all vaccination doses per Advisory Committee on Immunization Practices guidelines and by age at vaccination initiation, dichotomized as younger than 21 years vs 21 years or older.PPV of abnormal cervical cytology for risk of cervical intraepithelial neoplasia (CIN) 2 or more severe diagnosis.A total of 46 988 patients (mean [SD] age, 28.7 [4.5] years; 3058 [6.5%] Asian; 4159 [8.9%] Black or African American; 35 446 [75.4%] White) were included; 15 494 (33.0%) were at least partially vaccinated, and 4289 (9.1%) had abnormal cytology results during the study period. Among the individuals with abnormal cytology, the PPV for CIN 2 or more severe diagnosis was lower among vaccinated individuals (17.4%; 95% CI, 16.4%-18.4%) than unvaccinated individuals (21.3%; 95% CI, 20.4%-22.3%). Among vaccinated individuals, PPV was significantly lower among those completing vaccination (15.9%; 95% CI, 14.9%-17.0%) than those with incomplete vaccination (22.4%; 95% CI, 20.0%-25.0%), especially among those initiating vaccination when younger than 21 years (11.9%; 95% CI, 10.9%-12.9%) vs those initiating at age 21 years or older (30.7%; 95% CI, 27.3%-34.4%).Among a population with relatively low HPV vaccine coverage, the PPV of cervical cytology for CIN 2 or more severe diagnosis was significantly lower among vaccinated individuals. PPV will likely further decrease in the future as a population with higher HPV vaccination coverage ages into screening. Confirmation of these results will call for changes in screening strategies, particularly for completely vaccinated individuals who initiated vaccination when younger than 21 years.
Benefit of monoclonal antibodies in early treatment of COVID-19 after lung transplantation: a retrospective analysis in two centres
Authors: Jens Gottlieb, Martin Kolditz, Nils Gade, Tobias Welte, Nikolaus Kneidinger
Journal: European Respiratory Journal (2022)

<b>Treatment with monoclonal antibodies was associated with improved survival in COVID-19 after lung transplantation (LTx). Age was a negative independent predictor of survival in this cohort of 133 COVID-19 cases after LTx.</b>https://bit.ly/3kx5CBw
Reply to Drs. Shiha and Robinson
Authors: Marina de Benito Sanz, Francisco J. García-Alonso, Luis Hernández
Journal: Endoscopy (2022)

See also: Efficacy and safety of cold versus hot snare polypectomy for small (5–9 mm) colorectal polyps: a multicenter randomized controlled trialEndoscopy 2022; 54(01): 35-44DOI: 10.1055/a-1327-8357 See also: Abdominal pain post-hot snare polypectomy: could it have been avoided?Endoscopy 2022; 54(06): 628-628DOI: 10.1055/a-1819-1145
Abdominal pain post-hot snare polypectomy: could it have been avoided?
Authors: Mohamed G. Shiha, Richard J. Robinson
Journal: Endoscopy (2022)

See also: Efficacy and safety of cold versus hot snare polypectomy for small (5–9 mm) colorectal polyps: a multicenter randomized controlled trialEndoscopy 2022; 54(01): 35-44DOI: 10.1055/a-1327-8357 See also: Reply to Drs. Shiha and RobinsonEndoscopy 2022; 54(06): 629-629DOI: 10.1055/a-1823-1020
From Bridge to Destination? Ethical Considerations Related to Withdrawal of ECMO Support over the Objections of Capacitated Patients
Authors: Andrew Childress, Trevor Bibler, Bryanna Moore, Ryan H. Nelson, Joelle Robertson-Preidler, Olivia Schuman, Janet Malek
Journal: The American Journal of Bioethics (2022)

Extracorporeal membrane oxygenation (ECMO) is typically viewed as a time-limited intervention—a bridge to recovery or transplant—not a destination therapy. However, some patients with decision-making capacity request continued ECMO support despite a poor prognosis for recovery and lack of viability as a transplant candidate. In response, critical care teams have asked for guidance regarding the ethical permissibility of unilateral withdrawal over the objections of a capacitated patient. In this article, we evaluate several ethical arguments that have been made in favor of withdrawal, including distributive justice, quality of life, patients’ rights, professional integrity, and the Equivalence Thesis. We find that existing justifications for unilateral withdrawal of ECMO support in capacitated patients are problematic, which leads us to conclude that either: (1) additional ethical arguments are necessary to defend this approach or (2) the claim that it is not appropriate to use ECMO as a destination therapy should be questioned.
An emerging phenotype of pulmonary arterial hypertension patients carrying<i>SOX17</i>variants
Authors: David Montani, Benoit Lechartier, Barbara Girerd, Mélanie Eyries, Maria-Rosa Ghigna, Laurent Savale, Xavier Jaïs, Andrei Seferian, Mitja Jevnikar, Athénais Boucly, Marianne Riou, Julie Traclet, Ari Chaouat, Maryline Levy, Jerome Le Pavec, Elie Fadel, Frédéric Perros, Florent Soubrier, Martine Remy-Jardin, Olivier Sitbon, Damien Bonnet, Marc Humbert
Journal: European Respiratory Journal (2022)

The phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown.We report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network.20 patients and eight unaffected relatives were identified. The median (range) age at diagnosis was 17 (2-53) years, with a female:male ratio of 1.5. At diagnosis, most of the patients (74%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise, including a median pulmonary vascular resistance of 14.0 (4.2-31.5) WU. An associated congenital heart disease (CHD) was found in seven PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. 13 out of 16 patients (81%) for whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as anomalies of the bronchial and nonbronchial arteries. After a median (range) follow-up of 47 (1-591) months, 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathological analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci.PAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiological abnormalities. Pathological assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries.
Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration
Authors: Jinna Wu, Yuyu Chen, Zhiheng Liao, Hengyu Liu, Shun Zhang, Dongmei Zhong, Xianjian Qiu, Taiqiu Chen, Deying Su, Xiaona Ke, Yong Wan, Taifeng Zhou, Peiqiang Su
Journal: Molecular Therapy (2022)

Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.
Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia
Authors: Takaaki Konuma, Shohei Mizuno, Tadakazu Kondo, Yasuyuki Arai, Naoyuki Uchida, Satoshi Takahashi, Masatsugu Tanaka, Takuro Kuriyama, Shigesaburo Miyakoshi, Makoto Onizuka, Shuichi Ota, Yasuhiro Sugio, Yasushi Kouzai, Toshiro Kawakita, Hikaru Kobayashi, Yukiyasu Ozawa, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Masamitsu Yanada
Journal: Blood Cancer Journal (2022)

Abstract Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.
RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis
Authors: Jonathan Shintaku, Wolfgang M. Pernice, Wafaa Eyaid, Jeevan B. GC, Zuben P. Brown, Marti Juanola-Falgarona, Javier Torres-Torronteras, Ewen W. Sommerville, Debby M.E.I. Hellebrekers, Emma L. Blakely, Alan Donaldson, Ingrid van de Laar, Cheng-Shiun Leu, Ramon Marti, Joachim Frank, Kurenai Tanji, David A. Koolen, Richard J. Rodenburg, Patrick F. Chinnery, H.J.M. Smeets, Gráinne S. Gorman, Penelope E. Bonnen, Robert W. Taylor, Michio Hirano
Journal: Journal of Clinical Investigation (2022)

Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.
Crosstalk between IL‐15Rα<sup>+</sup>tumor‐associated macrophages and breast cancer cells reduces CD8<sup>+</sup>T cell recruitment
Authors: Wenlong Zhang, Qing Zhang, Nanfei Yang, Qian Shi, Huifang Su, Tingsheng Lin, Zhonglei He, Wenxin Wang, Hongqian Guo, Pingping Shen
Journal: Cancer Communications (2022)

Abstract Background Interleukin‐15 (IL‐15) is a promising immunotherapeutic agent owing to its powerful immune‐activating effects. However, the clinical benefits of these treatments are limited. Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance. Herein, this study aimed to obtain in‐depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression. Methods T‐cell killing assays and co‐culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL‐15. Western blotting, histological analysis, CRISPR‐Cas9 knockout, multi‐parameter flow cytometry, and tumor cell‐macrophage co‐injection mouse models were developed to examine the mechanism by which IL‐15Rα + tumor‐associated macrophages (TAMs) regulate breast cancer cell resistance to IL‐15. Results We found that macrophages contributed to the resistance of tumor cells to IL‐15, and tumor cells induced macrophages to express high levels of the α subunit of the IL‐15 receptor (IL‐15Rα). Further investigation showed that IL‐15Rα + TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1 (CX3CL1) in tumor cells to inhibit the recruitment of CD8 + T cells by releasing the IL‐15/IL‐15Rα complex (IL‐15Rc). Administration of an IL‐15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti‐ programmed cell death protein 1 (PD‐1) antibody immunotherapy. Interestingly, Granulocyte‐macrophage colony‐stimulating factor (GMCSF) induced γ chain (γc) expression to promote tumor cell‐macrophage crosstalk, which facilitated tumor resistance to IL‐15. Additionally, we observed that the non‐transcriptional regulatory function of hypoxia inducible factor‐1alpha (HIF‐1α) was essential for IL‐15Rc to regulate CX3CL1 expression in tumor cells. Conclusions The IL‐15Rc‐HIF‐1α‐CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumor microenvironment of breast cancer. Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.
Long non-coding RNA and RNA-binding protein interactions in cancer: Experimental and machine learning approaches
Authors: Hibah Shaath, Radhakrishnan Vishnubalaji, Ramesh Elango, Ahmed Kardousha, Zeyaul Islam, Rizwan Qureshi, Tanvir Alam, Prasanna R. Kolatkar, Nehad M. Alajez
Journal: Seminars in Cancer Biology (2022)

Understanding the complex and specific roles played by non-coding RNAs (ncRNAs), which comprise the bulk of the genome, is important for understanding virtually every hallmark of cancer. This large group of molecules plays pivotal roles in key regulatory mechanisms in various cellular processes. Regulatory mechanisms, mediated by long non-coding RNA (lncRNA) and RNA-binding protein (RBP) interactions, are well documented in several types of cancer. Their effects are enabled through networks affecting lncRNA and RBP stability, RNA metabolism including N6-methyladenosine (m6A) and alternative splicing, subcellular localization, and numerous other mechanisms involved in cancer. In this review, we discuss the reciprocal interplay between lncRNAs and RBPs and their involvement in epigenetic regulation via histone modifications, as well as their key role in resistance to cancer therapy. Other aspects of RBPs including their structural domains, provide a deeper knowledge on how lncRNAs and RBPs interact and exert their biological functions. In addition, current state-of-the-art knowledge, facilitated by machine and deep learning approaches, unravels such interactions in better details to further enhance our understanding of the field, and the potential to harness RNA-based therapeutics as an alternative treatment modality for cancer are discussed.
Dismantling Structural Racism in the Academic Residency Clinic
Authors: Rahul Vanjani, Andrea Pitts, Pranav Aurora
Journal: New England Journal of Medicine (2022)

approximately 150 members of the Young Lords executed the first of a series of occupations of Lincoln Hospital, an academic health center in the Bronx.Disenchanted with the care provided at Lincoln and its outpatient residency clinics, 1,2 the group demanded, among other changes, that the hospital cut its ties with academia; they believed that high turnover of physicians and inconsistency in care stemmed from this relationship.For these political activists, the relationship's failure was unassailable: it was imprinted on the Black and Brown corpses in the local morgue and on a hospital that, one of its doctors noted, "looked more like an abandoned factory than a center for the healing arts."No more competing interests, the Young Lords declared, as they collaborated with like-minded resident physicians to create the first-ever patient's bill of rights, including the right "to choose the doctor you want to have and to have the same doctor treat you all the time."Inspired by the Black Panther Party, the Young Lords were Puerto Rican and Black activists, originally based in Chicago and New York, who "sought to address issues of racism, incarceration and police brutality, employment, and inequality in education and public health, including sanitation, lead poisoning, access to decent health services, and hunger in the lives of poor children" 1 -issues that today would be called "structural racism."In January 1970, an article outlined the rationale for the hospital occupation that would occur 6 months later and demonstrated an early awareness of the structural racism pervading academic medical institutions."We learned that there are things called health empires: medical schools and private hospitals that through affiliations (contracts with the city) operate and run city hospitals," wrote the New York State Chapter of the Young Lords."These affiliations end
Summary of US Food and Drug Administration Chimeric Antigen Receptor (CAR) T-Cell Biologics License Application Approvals From a Statistical Perspective
Authors: Xue Lin, Shiowjen Lee, Poornima Sharma, Bindu George, John Scott
Journal: Journal of Clinical Oncology (2022)

The approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 marked a milestone in the development of oncology therapies. Since 2017, the breakthrough in treatment or even cure of previously intractable diseases represented by this new class of cancer treatments has continued with subsequent chimeric antigen receptor T (CAR T)-cell approvals. To date, the US Food and Drug Administration has approved five autologous CAR T-cell products for seven indications. A feature of autologous CAR T-cell products that differentiates them from traditional oncology drugs is that they need to be manufactured specifically for each patient. This feature has implications in study design, statistical analyses, and interpretation of study results. In this article, we share our experiences in the statistical review of CAR T-cell products and provide considerations for the design and statistical analyses of CAR T-cell trials. We also describe how the newly adopted estimand framework for clinical trials can help clarify nuanced issues in CAR T-cell trial design.
<i>M</i><i>ycobacterium tuberculosis</i>-specific CD4 T-cell scoring discriminates tuberculosis infection from disease
Authors: Andrej Mantei, Tim Meyer, Mariana Schürmann, Christiane Beßler, Harald Bias, David Krieger, Torsten Bauer, Petra Bacher, Johannes Helmuth, Hans-Dieter Volk, Dirk Schürmann, Alexander Scheffold, Christian Meisel
Journal: European Respiratory Journal (2022)

Background Rapid and reliable diagnostic work-up of tuberculosis (TB) remains a major healthcare goal. In particular, discrimination of TB infection from TB disease with currently available diagnostic tools is challenging and time consuming. This study aimed at establishing a standardised blood-based assay that rapidly and reliably discriminates TB infection from TB disease based on multiparameter analysis of TB antigen-reactive CD4 + T-cells acting as sensors for TB stage-specific immune status. Methods 157 HIV-negative subjects with suspected TB infection or TB disease were recruited from local tertiary care hospitals in Berlin (Germany). Peripheral blood mononuclear cells were analysed for CD4 + T-cells reactive to the Mycobacterium tuberculosis antigens purified protein derivative and early secretory antigenic target 6 kDa/culture filtrate protein 10. The activation state of TB antigen-reactive T-cells, identified by surface expression of CD154, was evaluated according to the expression profile of proliferation marker Ki-67 and activation markers CD38 and HLA-DR. Using data from 81 subjects with clinically confirmed TB infection (n=34) or culture-proven pulmonary or extrapulmonary TB disease (n=47), 12 parameters were derived from the expression profile and integrated into a scoring system. Results Using the scoring system, our assay (TB-Flow Assay) allowed reliable discrimination of TB infection from both pulmonary and extrapulmonary TB disease with high sensitivity (90.9%) and specificity (93.3%) as was confirmed by Monte-Carlo cross-validation. Conclusion With low time requirement, ease of sample collection, and high sensitivity and specificity both for pulmonary and extrapulmonary TB disease, we believe this novel standardised TB-Flow Assay will improve the work-up of patients with suspected TB disease, supporting rapid TB diagnosis and facilitating treatment decisions.